| Introduction
One of the major objectives in the pediatric intensive care unit (PICU) is
to treat children less invasively, thus avoiding physical and emotional suffering.
Sedatives are necessary to reduce the anxiety and agitation that result from the
admission to a hostile environment and from medical procedures. Analgesics are
used to treat pain secondary to surgical interventions and/or invasive methods,
besides the pain inflicted by the disease itself. Moreover, the combined use of
analgesics and sedatives allows patients to adapt to mechanical ventilation through
the hypnotic effects of these drugs, respiratory depression, and cough reflex.
However, the incorrect use of sedatives and analgesics may have negative effects,
causing a prolonged necessity for ventilatory support, increasing mortality and
morbidity, and lengthening the PICU stay.
The use of protocols that facilitate the selection of appropriate drugs, their
adequate administration and careful monitoring can improve the quality of sedation
and analgesia and prevent their adverse effects. There is a wide availability
of sedative and analgesic drugs that can be used in critically ill children, and
each one of them has advantages and disadvantages. Nevertheless, no analgesic
or sedative meets all the criteria of an ideal drug: rapid onset action, short
half-life, metabolization and elimination by organs that are less susceptible
to failure (liver and kidney), minimum secondary effects without hemodynamic or
respiratory involvement, no interaction with other drugs, and availability of
a specific antidote. When choosing a medication, one should bear the following
in mind: pharmacodynamics of the drug, its route of administration, secondary
effects, patient’s age, underlying disease, mechanical ventilation, nutritional
status, kidney and liver functions, cost, etc. There is a paucity of reviews and
practical guidelines for the use of sedatives, analgesics, and muscle relaxants
in critically ill children,
and most recommendations are based on experiences with adult patients.
This review provides practical guidelines that should be adapted to each patient,
based on the results from the objective and subjective monitoring analyses of
sedation and analgesia. Non-pharmacological treatment
Several non-pharmacological interventions can improve the routine of children
in the PICU, reducing their anxiety, improving their sleep-wake cycles, and minimizing
the necessity for sedative and analgesic drugs.
Music therapy has proven efficient in overcoming anxiety and increasing relaxation
of critically ill patients of any age, including preterm infants.
Other effective measures include noise control in the PICU, control of lighting
to maintain the day and night pattern and the sleep-wake cycle, massage, and communication,
if patient’s age and health status allow so. Sedative
drugs
Sedation is necessary in many PICU children, especially in
those who need ventilatory support. Sedation inhibits the neuroendocrine effects
caused by stress (hypertension, tachycardia, tachypnea and hyperglycemia), which
increase oxygen consumption and hinder synchronism with the ventilatory support
equipment. In addition, it prevents anxiety, which is accountable for sleep deprivation
and subsequent psychological disorders. Despite the fact that there are a wide
variety of drugs with different indications, there is no sedative that suits all
situations. Table 1 summarizes the basic characteristics of the most important
drugs.
The selection of the drug depends on several factors, such as age, disease, and
organ dysfunction/failure. The most commonly used drugs are: midazolam, lorazepam
and propofol, which are given in continuous intravenous doses. Midazolam is the
benzodiazepine of choice for continuous sedation of critically ill children. When
given quickly, it may reduce systemic vascular resistance and cause hypotension
in hypovolemic patients. However, its continuous intravenous infusion produces
few hemodynamic effects. For sedation, it is necessary to administer a bolus dose
prior to continuous infusion. Prolonged infusion produces tolerance, and hence
the necessity to gradually increase the dose in order to achieve the same sedative
effect. In this situation, midazolam should be combined with another sedative
(opioid, propofol or other). High doses may lead to “midazolam infusion
syndrome,” which consists of delayed arousal hours to days after discontinuation,
increasing the length of ventilatory support. In case of prolonged use for several
days, it is necessary to gradually decrease midazolam infusion so as not to induce
the withdrawal syndrome. Lorazepam has a similar effect to that of midazolam,
but its use in critically ill children is less documented.
The enteral route has been used for its administration in order to minimize the
need of continuous midazolam infusion and to prevent subsequent withdrawal syndrome. Table
1 -
Characteristics of sedatives most widely used in children The major
characteristics of propofol are its rapid onset of action and its rapid elimination
of adverse effects after withdrawal (“rapid arousal”). This can be
particularly useful in patients who require frequent neurological assessment (e.g.:
traumatic brain injury or convulsive status epilepticus). Propofol has
vasodilator properties and may cause reduced cardiac contractility and negative
chronotropic effects, especially in patients with hypovolemia and/or abnormal
myocardial contractility. For quick procedures (e.g.: respiratory endoscopy),
we use a loading dose of 1.5 mg/kg, with small bolus doses of 0.5 mg/kg, as necessary.
The maximum dose of propofol recommended for children is 4 mg/kg/hour.
Higher doses for prolonged periods are associated with the “propofol infusion
syndrome,” which consists of cardiogenic shock (reduced myocardial contractility
and conduction disorders) in addition to metabolic disorders (lactic acidosis,
hypertriglyceridemia) and/or rhabdomyolysis with high mortality. There are
numerous studies comparing both drugs.
Midazolam allows maintaining adequate sedation and amnesia levels at a low cost,
but its use is more complex, requiring more ventilatory support and showing a
greater association with the withdrawal syndrome after its discontinuation. Propofol
has a more rapid action and allows earlier weaning from the ventilator, but it
causes more vascular depression during induction, it is also more expensive and
should be given through an independent intravenous route. Midazolam is still the
drug of choice in patients who need sedation with intravenous infusion. Propofol
is the drug of choice for short procedures
and, in our setting, it is a safe and appropriate drug if low supplemental doses
are used in those patients in which adequate sedation is not obtained with midazolam. Etomidate
is one of the intravenous anesthesia-inducing agents that causes the fewest hemodynamic
alterations. For some time, it was the drug of choice for rapid and emergency
intubation in critically ill patients. However, recently, it has been contraindicated
as it causes suprarenal failure, even when it is used as a single dose for intubation.
In addition, it may cause trismus during anesthetic induction, so it must be used
with a neuromuscular blocking agent (NMBA). Therefore, its single and repeated
administration or infusion is contraindicated in septic patients, since it may
cause suprarenal failure. Other sedative drugs include barbiturates such
as pentobarbital and thiopental. Among other indications, they are recommended
in the treatment of refractory seizures and traumatic brain injury with severe
intracranial hypertension. Currently, they are seldom used in critically ill patients,
as they cause hemodynamic instability and accumulate in peripheral tissues after
prolonged infusion, delaying the patient’s arousal. Phenobarbital can also
be used as supplementary treatment in patients submitted to prolonged ventilatory
support in remarkable need for sedation. Chloral hydrate given orally or rectally
can be used as sedative in rapid interventions (e.g.: echocardiogram), but its
onset and length of action vary considerably. Analgesic
drugs Children admitted to the PICU have pain caused either by the underlying
disease or by the diagnostic or therapeutic procedures. More often than not, patients
receive insufficient analgesic treatment, even for painful procedures. A recent
study showed that 44% of children recalled the painful experiences they had been
put through during their PICU stay. As occurs with sedation, there is not such
a thing as an all-purpose analgesic, and the selection of drugs depends on numerous
factors. Table 2 summarizes the characteristics of the most commonly used drugs. Table
2 -
Characteristics of the drugs most commonly used in critically ill children Opioid
derivatives and non-steroidal anti-inflammatory drugs are the most widely used
analgesics in critically ill patients. Opioids are the drugs of choice for mechanically
ventilated patients,
especially if combined with benzodiazepines, since they have shown a synergistic
effect that allows reducing the dose of both medications.
Morphine and fentanyl are widely used in continuous infusion, but remifentanil,
tramadol and meperidine have been increasingly used as well. Morphine
has low solubility, which explains its delayed maximum effect on the central nervous
system (CNS) – 15 minutes – and its longer effect – 3-6 hours.
It is metabolized by the liver, originating two active metabolites that accumulate
in case of renal failure. When given intravenously, it may cause hypotension by
producing venodilation and by releasing histamine. Usually, its elimination half-life
is longer, but its elimination is smaller in newborn (NB) infants, compared to
other children and to adults. The greater difference is mostly perceived in preterm
NB infants. Nonetheless, less morphine binds to the protein in NB infants, leading
to a higher amount of morphine, increasing the risk for respiratory depression.
The elimination half-life and clearance similar to that of an adult is obtained
at 2 months of life. Fentanyl
is 60-100 times more potent than morphine. Its fat-solubility is higher, which
explains its rapid action and short duration, due to its fast distribution. If
given for a prolonged time, there is rapid tolerance and accumulation in the adipose
tissue; therefore, its half-life is longer than that of morphine. It does not
produce active metabolites. It does not release histamine, allowing for greater
hemodynamic stability than morphine. An infrequent adverse effect is chest wall
rigidity, which is related to the dose used, rate of infusion and age < 6 months. Remifentanil
is a fentanyl derivative with similar potency and rapid onset action. Its peak
effect is achieved in less than 3 minutes and it is short-acting (its effect disappears
within few minutes, being metabolized by nonspecific plasma esterases), regardless
of the length of its infusion and of the presence of liver and/or renal dysfunction.
This profile allows earlier extubation than other opioids and the use of higher
doses, in which the analgesic effects combine with sedative effects without any
risk of accumulation. Only approximately 30% of patients may need another sedative
at low doses in order to achieve the goals of sedation and analgesia. Disadvantages
include large economic cost, quick development of tolerance, and higher frequency
of hypotension compared to fentanyl.
Its use as continuous infusion has been more and more frequent, also among NB
and infants.
Due to its potency, hemodynamic stability and short action at low doses, fentanyl
is ideal for short painful procedures in children, especially in the PICU. Mild
to moderate pain can be effectively managed with non-opioid analgesics, such as
acetaminophen (paracetamol), or with non-steroidal anti-inflammatory drugs (NSAIDs).
Acetaminophen has a very good therapeutic power, with few contraindications. It
may be used in any age group, even in preterm infants, and it is possible to obtain
synergistic effects with other NSAIDs or opioids, due to its analgesic effect
on the central nervous system. NSAIDs
have analgesic and anti-inflammatory properties, both of which are useful in the
management of postoperative and chronic pain
or of mild to moderate pain. The most widely used NSAIDs are ketorolac, ketoprofen
and diclofenac. An advantage is that they do not cause respiratory depression
or sedation. The mechanism of action occurs through the inhibition of cyclooxygenase
(COX), the enzyme in charge of arachidonic acid metabolization.
In recent years, they have been increasingly used in combination with opioids
in the postoperative period, as they produce a synergistic analgesic effect that
allows better pain management with fewer secondary effects and lower doses. Ibuprofen
and naproxen are the most common NSAIDs in pediatrics.
They are not indicated in the initial stages of septic shock, due to their secondary
effects on the gastric mucosa, renal function and platelets. Metamizole is one
of the non-opioid analgesic drugs most widely used in European, South American
and African countries and can be used to treat moderate to severe pain, combined
with opioids in order to enhance the analgesic effects and delay the development
of tolerance. It may cause hypotension as a result of vasodilation if administered
as rapid intravenous infusion. The risk of agranulocytosis and bone marrow aplasia
is very low. At some centers, they are frequently used in continuous infusion
in the immediate postoperative period, including heart surgeries, with excellent
results. Tramadol is an atypical opioid structurally related to codeine.
Its double mechanism of action includes central inhibition of norepinephrine as
serotonin reuptake inhibitor and weak agonist action on the theta receptor, due
to an active metabolite. Tramadol is 10 to15 times less potent than morphine.
It is known for producing fewer side effects than other opioids. The use of tramadol
should be avoided in patients with seizures or traumatic brain injury or who are
being treated with drugs that lower the seizure threshold. In general, tramadol
is a safe and efficient analgesic in the management of mild to moderate pain in
children. Analgesic
and sedative drugs Ketamine It is a phencyclidine derivative
that produces dissociative anesthesia. It has analgesic effects, even at lower
doses than the sedative dose. It is a potent analgesic at subanesthetic doses
and regularly used in painful procedures in children in the emergency room (e.g.:
fracture reduction, burn dressings) and in the PICU.
Its half-life ranges from 2-3 hours, and may be extended if continuous infusion
is used or in case of liver failure. Unlike other sedative drugs, it activates
the sympathetic nervous system (by releasing endogenous norepinephrine), with
increase in heart rate, in vascular resistance, and with bronchodilation. Although
it has a negative inotropic effect, sympathetic stimulation runs counter to this
effect, except in cases of catecholamine-refractory cardiogenic shock. The difference
between intramuscular and intravenous administration lies only in the onset of
action (1-2 minutes and 5-10 minutes). Intravenous doses provide around 10 minutes
of sedation and analgesia for each mg/kg, i.e., 1 mg/kg of IV ketamine produces
analgesia and sedation for 10 minutes, whereas 2 mg/kg produces approximately
20 minutes of analgesia and sedation. However, the residual effect may last for
2-3 hours. One IV dose of 1-2 mg/kg is usually well tolerated in procedures that
involve a larger amount of pain, such as fracture reduction. Ketamine in
continuous infusion combined with benzodiazepines can be used in hemodynamically
unstable critically ill patients, providing good sedation and analgesia and reducing
the dose of catecholamines. Ketamine is mostly useful for sedation and analgesia
in invasive procedures, and is often used in combination with midazolam and as
an anesthesia inducing agent in emergency intubation in status asthmaticus. Adrenergic
alpha-2-agonists Clonidine and dexmedetomidine have a sedative and analgesic
effect due to their action on alpha-2 receptors.
Clonidine causes minor respiratory depression. There are some contradictory reports
in the literature with regard to the effects of dexmedetomidine on ventilatory
function in some (human and animal) studies, suggesting mild respiratory depression,
reduction of the minute ventilation and reduction of CO2 response,
whereas other reports do not show this effect. Clonidine
has been used as premedication before surgery, for peripheral blockade, as an
analgesic in intrathecal perfusion and for the control of tolerance and of the
deprivation syndrome of other sedatives.
Its oral administration is used in several PICUs for the prevention and treatment
of deprivation syndrome of other sedatives. Dexmedetomidine in intravenous infusion
has sedative and analgesic effects, minimizing the need for opioids. It may be
very useful in the immediate postoperative period, facilitating early extubation.
It is an alpha-2-agonist receptor that acts centrally, with affinity for a receptor
that is eight times larger than clonidine. The use of dexmedetomidine was initially
considered as a sedative to be used in mechanically ventilated adults, but now
its use in children is also documented. Although dexmedetomidine has been primarily
investigated for its sedative effect, it apparently has analgesic effects that
are appropriate for cases where opioids are needed, therefore allowing for a lower
opioid use. Monitoring
of sedation and analgesia The monitoring of sedation level is key
to avoiding undersedation, which causes suffering to the patient, and oversedation,
which delays extubation. Clinical scores are the most common tools for monitoring
the levels of sedation. However, these scores are limited, since they are subjective,
their assessment is intermittent, they sometimes interrupt patient’s rest
and sometimes give more importance to pain sensitivity than to the sedation level.
Moreover, their usefulness is quite limited in deep levels of sedation and in
patients with muscle relaxation. The Ramsay and Comfort scores are the most widely
used tools for determining the level of sedation in pediatrics. The Ramsay score
can be easily and quickly applied, but its use has not been validated in children,
and it is not useful in relaxed patients. In addition, it uses auditory and painful
stimuli to evaluate responses, which increases its subjectivity. The Comfort score
was designed for mechanically ventilated children and does not require the use
of any stimulus for evaluation. Nevertheless, it is more time-consuming and complex,
it assesses both objective and subjective parameters, it includes variables such
as heart rate and blood pressure, which change in critically ill patients as a
result of several other factors, and it has not been validated in children with
muscle relaxation. A recent study has described a simplified Comfort score with
the same value as the original score, in which physiological variables were eliminated. In
the last few years, several methods have been developed that allow objectively
assessing the level of consciousness by analyzing electroencephalographic findings,
such as the bispectral index (BIS), auditory evoked potentials of intermediate
latency and analysis of electroencephalographic (EEG) spectra.
These instruments have been developed and validated to assess the depth of anesthesia
in patients submitted to surgical interventions; however, there is a paucity of
studies on their usefulness in critically ill patients. BIS is the most frequently
used, as it continually assesses EEG findings and provides a numerical measurement
of the sedation level, ranging from 0 (electrical silence) to 100 (awake). BIS
allows improved and continuous monitoring of patients that need deep sedation
and neuromuscular blockade. The assessment of pain in the PICU is much more
difficult, especially in mechanically ventilated sedated patients. Quite often,
it is not possible to make a distinction between pain and anxiety, and both should
be treated simultaneously. Furthermore, pain expression in newborns and infants
is undifferentiated. To assess pain, different scales have to be used for each
stage of childhood. At the preverbal stage (NB to 3 years), the scales use mainly
facial expression and motor and physiological response, such as crying. Parents’
opinions must be taken into account in order to distinguish between reactions
caused by pain and others that are caused by anything else.
At the verbal stage (3-8 years), it is possible to use self-information through
pictures and face drawings. After the age of 8 years, the verbal, numerical, graphic,
and visual analog scales can be used. Neuromuscular
blocking agents In certain situations, in addition to sedative and
analgesic drugs, the use of neuromuscular blocking agents (NMBAs) is necessary.
They are subdivided into depolarizing and non-depolarizing agents. Table 3 shows
the most widely used NMBAs. Table 3
-
Characteristics of the neuromuscular blocking agents most frequently used in children Succinylcholine
is still the most widely used muscle relaxant for emergency intubations, due to
its rapid action, whereas rocuronium is the most efficient alternative with fewer
secondary effects. Muscle relaxants are also useful in some patients in
which sedation and analgesia are not enough to allow adaptation to mechanical
ventilation. They increase the compliance of the respiratory system, reducing
the pressure that is necessary to ventilate and minimize oxygen consumption. It
has been suggested that their early use in mechanically ventilated patients with
acute respiratory distress syndrome (ARDS) can prevent progression of inflammation
and ventilator-induced lung injury. Vecuronium is more widely used in critically
ill patients,
as it does not cause hemodynamic changes and does not release histamine. It has
an intermediate half-life, it does not often bind to proteins, has a high distribution
volume and is metabolized by the liver into active metabolites that are eliminated
by the kidneys. This explains why its effects last longer in patients with renal
and/or liver dysfunction. All patients on muscle relaxants must be previously
sedated to avoid anxiety of involuntary immobilization in alert patients. Neuromuscular
blocking agents must be given at the least effective dose and for the shortest
time. Their main risk includes residual neuromuscular blockade and accumulation
due to prolonged administration, which may lead to muscle weakness and neuromyopathy,
being more frequent when combined with the use of corticosteroids in patients
with sepsis, renal or liver failure. Maintenance of a minimum depth of neuromuscular
blockade can reduce the incidence of complications. The train of four (TOF) is
the most commonly used method to assess the depth of neuromuscular blockade. It
consists in applying four supramaximal, consecutive electrical stimuli on a peripheral
nerve using a neurostimulator.
Under normal conditions, this stimulus produces four identical contractions in
the muscle zone of the stimulated nerve. In the presence of NMBA and according
to the level of blockade generated, the number of responses diminishes. In general,
neuromuscular blockade is adequate if there are two or three contractions in response
to the four stimuli. Withdrawal syndrome The withdrawal
syndrome results from sudden discontinuation of sedative and analgesic drugs in
patients with physical tolerance due to prolonged administration of such drugs.
The signs and symptoms vary substantially in terms of presentation and severity,
depending on the drug and on the patient’s status. Among these signs and
symptoms are CNS activation (irritability, abnormal reflexes, tremors, clonus,
hypertonicity, delirium, and seizures), gastrointestinal disorders (gastrointestinal
intolerance, nausea, vomiting and diarrhea) and activation of the sympathetic
nervous system (tachycardia, hypertension and tachypnea). Finnegan’s score
can be used to assess their presentation and intensity. This
syndrome has been described in the administration of most sedative and analgesic
drugs, such as opioids, benzodiazepines, barbiturates, and propofol. The withdrawal
syndrome occurs in 50% of the cases with an overall fentanyl dose greater than
1.5 mg/kg or administration longer than 5 days, rising to 100% when the overall
dose is greater than 2.5 mg/kg or with an administration longer than 9 days. The
incidence of this syndrome increases significantly with an overall midazolam dose
greater than 60 mg/kg, and with an overall pentobarbital dose greater than 25
mg/kg. Different
methods are used to prevent the development of the withdrawal syndrome, such as
gradual reduction in doses,
methadone administration,
subcutaneous use of fentanyl and midazolam and avoidance of continuous intravenous
sedation. Recently, it has been proposed that administration in adults be completely
discontinued for some time every day after continuous infusion of sedative and
analgesic drugs. In some studies, this measure managed to reduce the length of
mechanical ventilation and ICU stay.
This measure can certainly lead to a higher risk of acute deprivation, pain, and
agitation, and because of that, it is not frequently used in pediatric patients.
It is therefore recommended that the level of sedation be reduced every day for
some hours without withdrawing the sedative and analgesic drugs and that the new
objective methods be used to monitor the level of consciousness. The most widely
used method consists of the progressive replacement of continuous intravenous
drugs with long-acting enteral drugs. The most common drugs include enteral methadone
and morphine, lorazepam, chlorazepate, and alpha-2-agonists (e.g.: clonidine).
In our PICU, we gradually weaned our patients from continuous fentanyl and midazolam
perfusion for over 7 days in order to prevent the withdrawal syndrome, and we
replaced them with methadone and chlorazepate dipotassium given enterally every
6-8 hours. In case of signs of withdrawal syndrome or if the dose of intravenous
sedatives could not be reduced, then we gave enteral clonidine. Protocols
in medical practice The introduction of clinical guidelines for
the management of sedation and analgesia in the ICU has been associated with better
sedative and analgesic control, with reduction in the length of mechanical ventilation
and in ICU stay, as well as with a reduction in expenditures on sedative and analgesic
drugs. Theoretically, the continuous administration of analgesic and sedative
drugs is more appropriate. Moreover, this is less demanding in terms of care and
prevents undersedation. The strict use of protocols for sedation using continuous
perfusion can result in larger need for mechanical ventilation, longer ICU and
hospital stay, and larger number of reintubations. Therefore, it is important
that every unit use one sedation protocol and that this protocol be adapted to
each patient in each situation, based on the monitoring of his/her health status
and level of sedation. The protocol should clearly establish the regimen for initial
administration, dose escalation and reduction, indications for additional bolus
doses and the method for discontinuation of sedation. Table 4 summarizes the protocol
for sedation and analgesia adopted by the PICU of Gregório Maragnón
hospital, in Spain. Table 4 -
Protocol for sedation and analgesia (PICU of Gregorio Marañón hospital,
Spain) |
